The Effect of Tuberculosis Infection on Pancreatic Beta-Cell Function in Patients with Type 2 Diabetes Mellitus

Objective: The aim of this study is to investigate how individuals with type 2 diabetes mellitus’ pancreatic β-cell function index and insulin resistance index are affected by tuberculosis infection. Methods: The study group consisted of 89 patients with type 2 diabetes mellitus and tuberculosis infection who were admitted to Jingzhou Chest Hospital between March 2019 and March 2021. Gender and duration of diabetes were matching conditions. The control group was made up of 89 patients with type 2 diabetes who were admitted to Jingzhou Central Hospital’s endocrinology department during the same period. The two patient groups provided general information such as gender, age, length of diabetes, and blood biochemical indexes such as glycosylated hemoglobin (HbA1c), fasting glucose (FPG), and fasting C-peptide (FC-P). The HOMA calculator was used to calculate the HOMA-β and the HOMA-IR, and intergroup comparisons and correlation analyses were carried out. Results: Regarding gender, age, disease duration, FC-P, and HbA1c, the differences between the two groups were not statistically significant (P > 0.05). However, BMI, FPG, HOMA-β, and HOMA-IR showed statistically significant differences (P < 0.05). In comparison to the control group, the study group’s HOMA-β was lower and its HOMA-IR was greater. According to Spearman’s correlation analysis, HOMA-β had a negative association (P th FPG, HbA1c, and the length of the disease, and a positive correlation with BMI and FC-P. A positive correlation was found between HOMA-IR and BMI, FPG, and FC-P (P < 0.01), as well as a correlation with the length of the disease (P > 0.05) and HbA1c. Conclusions: In type 2 diabetes mellitus combined with tuberculosis infection, the patients had higher FPG levels and lower FC-P levels, the secretory function of pancreatic β-cells was more severely impaired, and insulin resistance was more obvious.

MicroRNA-34c regulates porcine granulosa cell function by targeting forkhead box O3a

Granulosa cells（GCs） are somatic cells of ovary, the behaviors of GCs are important for ovarian function. MicroRNAs（miRNAs） are a class of endogenous 18–24 nucleotide（nt） non-coding RNAs, some of which have been shown to be important regulators of GCs function. miR-34c involved in the regulation of various biological processes and was identified to be a pro-apoptotic and anti-proliferative factor in many cell types. However, the roles of miR-34c in GCs function remain unknown. In this study, we used Annexin V-FITC and Ed U assays to demonstrate that miR-34c exerted pro-apoptotic and anti-proliferative effects in porcine GCs. Dual-luciferase reporter assays, quantitative real-time PCR（q RT-PCR） and Western blotting identified Forkhead box O3a（Fox O3a） as a direct target gene of miR-34c. The overexpression of FoxO3a rescued the phenotypic change caused by miR-34c in porcine GCs. In conclusion, miR-34c regulate the function of porcine GCs by targeting FoxO3a.

Bilayer nicorandil-loaded small-diameter vascular grafts improve endothelial cell function via PI3K/AKT/eNOS pathway

For the surgical treatment of cardiovascular disease(CVD),there is a clear and unmet need in developing small-diameter(diameter<6 mm)vascular grafts.In our previous work,sulfated silk fibroin(SF)was successfully fabricated as a potential candidate for preparing vascular grafts due to the great cytocompatibility and hemocompatibility.However,vascular graft with single layer is difficult to adapt to the complex internal environment.In this work,polycaprolactone(PCL)and sulfated SF were used to fabricate bilayer vascular graft(BLVG)to mimic the structure of natural blood vessels.To enhance the biological activity of BLVG,nicorandil(NIC),an FDA-approved drug with multi-bioactivity,was loaded in the BLVG to fabricate NIC-loaded BLVG.The morphology,chemical composition and mechanical properties of NIC-loaded BLVG were assessed.The results showed that the bilayer structure of NIC-loaded BLVG endowed the graft with a biphasic drug release behavior.The in vitro studies indicated that NIC-loaded BLVG could significantly increase the proliferation,migration and antioxidation capability of endothelial cells(ECs).Moreover,we found that the potential biological mechanism was the activation of PI3K/AKT/eNOS signaling pathway.Overall,the results effectively demonstrated that NIC-loaded BLVG had a promising in vitro performance as a functional small-diameter vascular graft.

Regulation of neural stem/progenitor cell functions by P2X and P2Y receptors

Neural stem/progenitor cells：Radial glial cells constitute multipotent cells in the ventricular zone,lining the wall of the lateral ventricle of the embryonic brain.They have the capacity to give rise to cells belonging to all three major linages（neurons,astrocytes and oligodendrocytes）of the nervous system（Tang and Illes,2017）.

THE CHANGES OF PANCREATIC ACINAR CELL FUNCTION IN ACUTE NECROTIZING PANCREATITIS OF RATS

ObjectiFe To evaluate the changes of pancreatic acinar cell functions in the rats with acutenecrotizing pancreatitis (ANP). methods Seventy SD rats were randomized into two groups: experimental group(n=35) and control group (n=35). To prepare the experimental model, the retrograde injection of 5% sodiumtaurocholate into the pancreatic duct was used for inducing ANP. Radioactive tracing by L -3H-phenylalanineand autoradiography were performed for scoring the differences of changes of amino acid uptake, enzyme-proteinsynthesis and output from acinar cells in rats between both groups. Results No changes were observed in aminoacid uptake and enzyme -protein synthesis in rats with dotted and haemorrhagic necrotizing foci as compared withcontrol group. However, accumulated zymogen granules in the interstitial of acinar cells were seen in theexperimental group. Conclusion It indicates that in experimental ANP rats, the functions of acinar cells in bothamino acid uptake and protein synthesis were essentially normal, but the pathway of enzyme output was affectedinto ectopic secretion through the bottom or lateral cellular membrane of pancreatic acinar cell.

Pancreatic fat and β-cell function in overweight/obese children with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease(NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction(HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue(VAT), pancreatic fat fraction(PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance(HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index(WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either:(1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/d L to < 126 mg/d L;(2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/d L and < 200 mg/d L; or(3) hemoglobin A1 c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index(BMI)-SD score, and VAT. In multiple regression analysis withWBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI(standardized coefficient B,-0.398; P = 0.001) as well as HOMA-IR(0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes(OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.

EFFECTS OF GLUCAGON ON ISLET β CELL FUNCTION IN PATIENTS WITH DIABETES MELLITUS

Objective To evaluate islet β cell response to intravenous glucagon(a non-glucose secretagogue)stimulation in diabetes mellitus.Methods Nineteen patients with type 1 diabetes(T1D)and 131 patients with type 2 diabetes(T2D)were recruited in this study.T2D patients were divided into two groups according to therapy:36 cases treated with insulin and 95 cases treated with diet or oral therapy.The serum C-peptide levels were determined at fasting and six minutes after intravenous injection of 1 mg of glucagon.Results Both fasting and 6-minute post-glucagon-stimulated C-peptide levels in T1D patients were significantly lower than those of T2D patients(0.76±0.36 ng/mL vs.1.81±0.78 ng/mL,P<0.05;0.88±0.42 ng/mL vs.3.68±0.98 ng/mL,P<0.05).In T1D patients,the C-peptide level after injection of glucagon was similar to the fasting level.In T2D,patients treated with diet or oral drug had a significantly greater fasting and stimulated C-peptide level than those patients received insulin therapy(2.45±0.93 ng/mL vs.1.61±0.68 ng/mL,P<0.05;5.26±1.24 ng/mL vs.2.15±0.76 ng/mL,P<0.05).The serum C-peptide level after glucagon stimulation was positively correlated with C-peptide levels at fasting in all three groups(r=0.76,P<0.05).Conclusions The 6-minute glucagon test is valuable in assessing the function of islet β cell in patients with diabetes mellitus.It is helpful for diagnosis and treatment of diabetes mellitus.

Six-year follow-up of pancreatic β cell function in adults with latent autoimmune diabetes

AIM: To investigate the characteristics of the progression of islet β cell function in Chinese latent autoimmune diabetes in adult (LADA) patients with glutamic acid decarboxylase antibody (GAD-Ab) positivity, and to explore the prognostic factors for β cell function. METHODS: Forty-five LADA patients with GAD-Ab positivity screened from phenotypic type 2 diabetic (T2DM) patients and 45 T2DM patients without GAD-Ab matched as controls were followed-up every 6 mo. Sixteen patients in LADA1 and T2DM1 groups respectively have been followed-up for 6 years, while 29 patients in LADA2 and T2DM2 groups respectively for only 1.5 years. GAD-Ab was determined by radioligand assay, and C-peptides (CP) by radioimmune assay.RESULTS: The percentage of patients whose fasting CP(FCP) decreased more than 50% compared with thebaseline reached to 25.0% at 1.5th year in LADA1 group, and FCP level decreased (395.8±71.5 vs 572.8±72.3 pmol/L, P＜0.05) at 2.5th year and continuously went down to the end of follow-up. No significant changes of the above parameters were found in T2DM1 group. The average decreased percentages of FCP per year in LADA and T2DM patients were 15.8% (4.0-91.0%) and 5.2% (-3.5 to 35.5%, P= 0.000) respectively. The index of GAD-Ab was negatively correlated with the FCP in LADA patients (rs= -0.483, P = 0.000). The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (rs = 0.408, -0.301 and -0.523 respectively, P＜0.05). Moreover, GAD-Ab wasthe only risk factor for predicting βcell failure in LADA patients (B = 1.455, EXP (B) = 4.283, P = 0.023). CONCLUSION: The decreasing rate of islet β cell function in LADA, being highly heterogeneous, is three times that of T2DM patients. The titer of GAD-Ab is an important predictor for the progression of islet β cell function, and age at onset and BMI could also act as the predictors.

Pancreatic fat and β-cell function in overweight/obesechildren with nonalcoholic fatty liver disease

AIM To investigate the impact of telaprevir-basedtriple therapy on the serum alpha-fetoprotein （AFP）level of chronic hepatitis C patients.METHODS： A total of 210 patients with chronichepatitis C genotype 1 of high viral load （baselineserum hepatitis C virus RNA 〉 5.0 log10 IU/mL） weredivided into two groups by type of treatment： tripletherapy with telaprevir, pegylated-interferon-α （PEGIFNα）,and ribavirin （RBV） for 24 wk （n = 88）, or dualtherapy with PEG-IFNα and RBV for 48 wk （n = 122）.The relationship between virological response and thechange in the serum AFP level from baseline to 24 wkafter the end of treatment was examined.RESULTS： No significant difference in mean baselineAFP level was found between the triple and dualtherapy groups （8.8 ng/mL vs 7.8 ng/mL）. Tripletherapy produced significant declines in the AFP levelin sustained virological response （SVR） and non-SVRpatients （7.8 ng/mL at baseline to 3.5 ng/mL at 24 wkafter the end of treatment, P 〈 0.001 and 14.3 ng/mLto 9.5 ng/mL, P = 0.004, respectively）. In contrast,dual therapy resulted in a significant decline in AFPlevel only in SVR patients （4.7 ng/mL to 2.8 ng/mL, P AbstractAIM： To investigate the impact of telaprevir-basedtriple therapy on the serum alpha-fetoprotein （AFP）level of chronic hepatitis C patients.METHODS： A total of 210 patients with chronichepatitis C genotype 1 of high viral load （baselineserum hepatitis C virus RNA 〉 5.0 log10 IU/mL） weredivided into two groups by type of treatment： tripletherapy with telaprevir, pegylated-interferon-α （PEGIFNα）,and ribavirin （RBV） for 24 wk （n = 88）, or dualtherapy with PEG-IFNα and RBV for 48 wk （n = 122）.The relationship between virological response and thechange in the serum AFP level from baseline to 24 wkafter the end of treatment was examined.RESULTS： No significant difference in mean baselineAFP level was found between the triple and dualtherapy groups （8.8 ng/mL vs 7.8 ng/mL）. Tripletherapy produced significant declines in the AFP levelin sustained virological response （SVR） and non-SVRpatients （7.8 ng/mL at baseline to 3.5 ng/mL at 24 wkafter the end of treatment, P 〈 0.001 and 14.3 ng/mLto 9.5 ng/mL, P = 0.004, respectively）. In contrast,dual therapy resulted in a significant decline in AFPlevel only in SVR patients （4.7 ng/mL to 2.8 ng/mL,

Level of Fasting C-Peptide as a Predictor of <i>β</i>-Cell Function in Sudanese Patients with Type 2 Diabetes Mellitus

Objective: In this study, we assessed the level of fasting C-peptide as a predictor of β-cell function and insulin resistance in patients with Type 2 diabetes mellitus (T2DM), Gezira State-Sudan. Methods: In this cross-sectional study, 100 T2DM patients attending the Diabetic patients care Centre were recruited, thirty five patients were males and sixty five were females, the mean age of the patients was 50.29 ± 0.456 years, and body mass index (BMI) was 26.54 ± 0.437. We estimated β-cell function using fasting C-peptide levels;homeostatic model assessment for β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated from C-peptide and fasting blood glucose (FBG). Results: C-peptide was significantly and positively correlated with HOMA-B and HOMA-IR. FBG also showed significant negative correlation with HOMA-B, but was positively and significantly correlated with HOMA-IR. HbA1c was negatively and significantly correlated with HOMA-B. Patients with low C-peptide levels had increased FBG and HbA1c level, while patients with high C-peptide levels were having high HOMA-IR and HOMA-B. Conclusions: Fasting C-peptide is a useful marker of pancreatic β-cell function, and its circulating levels could be used to evaluate insulin secretion and insulin resistance. Moreover, HOMA-IR is an effective index to achieve glycemic control by appropriate pharmacologic treatment of T2DM.

Improved <i>β</i>-cell function rather than increased insulin sensitivity is associated with reduction in hemoglobin A1c in newly diagnosed Type 2 diabetic patients treated with metformin

β-cell dysfunction and decreased insulin sensitivity are believed to be two chief mechanisms that participate in deterioration of glycemic control in Type 2 diabetes. Meformin is widely accepted as the first-line oral agent in the treatment of Type 2 diabetes. However, the relative contributions of improved β-cell function and increased insulin sensitivity to reduction in hemoglobin A1c (HbA1c) are unclear in newly diagnosed Type 2 diabetic patients treated with metformin. We investigated β-cell function and insulin sensitivity in relation to reduction in HbA1c in 20 newly diagnosed Type 2 diabetic patients (17 men and 3 women, mean age 49.1 ± 10.1 years, mean body mass index 26.4 ± 5.2 kg/m2) treated with metformin for 16 weeks. We used homeostasis model assessment (HOMA) 2%B and HOMA2%S as estimates of β-cell function and insulin sensitivity, respectively. Median HOMA2%B and HOMA2%S significantly increased from 38.8 to 68.8 (p p = 0.004), respectively. In univariate regression analysis, reduction in HbA1c was highly correlated with change in HOMA2%B (r = -0.866, p < 0.001), but not with that in HOMA2%S (r = -0.264, p = 0.260). Furthermore, multivariate regression analysis with reduction in HbA1c as a dependent variable showed that increase in HOMA2%B but not that in HOMA2%S was a significant dependent variable (β = -0.847, p β-cell function rather than increased insulin sensitivity is associated with reduction in HbA1c. These results suggest that metformin reduces HbA1c chiefly through improved β-cell function rather than increased insulin sensitivity in patients with newly diagnosed Type 2 diabetes.

The association of depression and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes

Background: Diabetes and diabetes-related complications are major causes of morbidity and mortality in the United States. Depressive symptoms and perceived stress have been identified as possible risk factors for beta cell dysfunction and diabetes. The purpose of this study was to assess associations between depression symptoms and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes. Participants and Methods: Informed consent and data were available for 462 participants (231 African Americans and 231 Haitian Americans) for this cross-sectional study. A demographic questionnaire developed by the Primary Investigator was used to collect information regarding age, gender, smoking, and ethnicity. Diabetes status was determined by self-report and confirmed by fasting blood glucose. Anthropometrics (weight, and height and waist circumference) and vital signs (blood pressure) were taken. Blood samples were drawn after 8 10 hours over-night fasting to measure lipid panel, fasting plasma glucose and serum insulin concentrations. The homeostatic model assessment, version 2 (HOMA2) computer model was used to calculate beta cell function. Depression was assessed using the Beck Depression Inventory-II (BDI-II) and stress levels were assessed using the Perceived Stress Scale (PSS). Results: Moderate to severe depressive symptoms were more likely for persons with diabetes (p = 0.030). There were no differences in perceived stress between ethnicity and diabetes status (p = 0.283). General linear models for participants with and without type 2 diabetes using beta cell function as the dependent variable showed no association with depressive symptoms and perceived stress;however, Haitian Americans had significantly lower beta cell function than African Americans both with and without diabetes and adjusting for age, gender, waist circumference and smoking. Further research is needed to compare these risk factors in other race/ethnic groups.

A review on cell damage,viability,and functionality during 3D bioprinting

Three-dimensional(3D)bioprinting fabricates 3D functional tissues/organs by accurately depositing the bioink composed of the biological materials and living cells.Even though 3D bioprinting techniques have experienced significant advancement over the past decades,it remains challenging for 3D bioprinting to artificially fabricate functional tissues/organs with high post-printing cell viability and functionality since cells endure various types of stress during the bioprinting process.Generally,cell viability which is affected by several factors including the stress and the environmental factors,such as pH and temperature,is mainly determined by the magnitude and duration of the stress imposed on the cells with poorer cell viability under a higher stress and a longer duration condition.The maintenance of high cell viability especially for those vulnerable cells,such as stem cells which are more sensitive to multiple stresses,is a key initial step to ensure the functionality of the artificial tissues/organs.In addition,maintaining the pluripotency of the cells such as proliferation and differentiation abilities is also essential for the 3D-bioprinted tissues/organs to be similar to native tissues/organs.This review discusses various pathways triggering cell damage and the major factors affecting cell viability during different bioprinting processes,summarizes the studies on cell viabilities and functionalities in different bioprinting processes,and presents several potential approaches to protect cells from injuries to ensure high cell viability and functionality.

TM9SF1 promotes bladder cancer cell growth and infiltration

BACKGROUND Bladder cancer(BC)is the most common urological tumor.It has a high recur-rence rate,displays tutor heterogeneity,and resists chemotherapy.Furthermore,the long-term survival rate of BC patients has remained unchanged for decades,which seriously affects the quality of patient survival.To improve the survival rate and prognosis of BC patients,it is necessary to explore the molecular mechanisms of BC development and progression and identify targets for treatment and intervention.Transmembrane 9 superfamily member 1(TM9SF1),also known as MP70 and HMP70,is a member of a family of nine transmembrane superfamily proteins,which was first identified in 1997.TM9SF1 can be expressed in BC,but its biological function and mechanism in BC are not clear.AIM To investigate the biological function and mechanism of TM9SF1 in BC.Overexpression of TM9SF1 increased the in vitro proliferation,migration,and invasion of BC cells by promoting the entry of BC cells into the G2/M phase.Silencing of TM9SF1 inhibited in vitro proliferation,migration,and invasion of BC cells and blocked BC cells in the G1 phase.CONCLUSION TM9SF1 may be an oncogene in BC.

The Chinese patent medicine, Jin-tang-ning, ameliorates hyperglycemia through improving β cell function in pre-diabetic KKAy mice

Jin-tang-ning(JTN), a Chinese patent medicine, mainly comprised of Bombyx mori L., has been proved to show α-glucosidase inhibitory efficacy and clinically effective for the treatment of type 2 diabetes(T2 DM). Recently, we have reported that JTN could ameliorate postprandial hyperglycemia and improved β cell function in monosodium glutamate(MSG)-induced obese mice,suggesting that JTN might play a potential role in preventing the conversion of impaired glucose tolerance(IGT) to T2 DM. In this study, we evaluated the effect of JTN on the progression of T2 DM in the pre-diabetic KKAy mice. During the 10 weeks of treatment,blood biochemical analysis and oral glucose tolerance tests were performed to evaluate glucose and lipid profiles. The β cell function was quantified using hyperglycemic clamp at the end of the study. JTN-treated groups exhibited slowly raised fasting and postprandial blood glucose levels, and also ameliorated lipid profile. JTN improved glucose intolerance after 8 weeks of treatment. Meanwhile, JTN restored glucose-stimulated first-phase of insulin secretion and induced higher maximum insulin levels in the hyperglycemic clamp.Thus, to investigate the underlying mechanisms of JTN in protecting β cell function, the morphologic changes of the pancreatic islets were observed by optical microscope and immunofluorescence of hormones(insulin and glucagon). Pancreatic protein expression levels of key factors involving in insulin secretion-related pathway and ER stress were also detected by Western blot. Pre-diabetic KKAy mice exhibited a compensatory augment in β cell mass and abnormal α cell distribution. Long-term treatment of JTN recovered islet morphology accompanied by reducing α cell area in KKAy mice. JTN upregulated expression levels of glucokinase(GCK), pyruvate carboxylase(PCB) and pancreas duodenum homeobox-1(PDX-1), while down-regulating C/EBP homologous protein(Chop)expression in pancreas of the hyperglycemic clamp, which indicated the improvement of mitochondrial metabolism and relief of endoplasmic reticulum(ER) stress of β cells after JTN treatment. These results will provide a new insight into exploring a novel strategy of JTN for protecting β cell function and preventing the onset of pre-diabetes to T2 DM.

Insulin sensitivity,βcell function,and adverse pregnancy outcomes in women with gestational diabetes

Background: The potential impact of β cell function and insulin sensitivity on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains uncertain. We aimed to investigate the association between β cell dysfunction, insulin resistance, and the composite adverse pregnancy outcomes.Methods: This observational study included 482 women diagnosed with GDM during pregnancy. Quantitative metrics on β cell function and insulin sensitivity during pregnancy were calculated using traditional equations. The association of β cell dysfunction and insulin resistance with the risk of the composite adverse pregnancy outcomes was investigated using multivariable-adjusted logistic regression models.Results: Multivariable-adjusted odds ratios (ORs) of adverse pregnancy outcomes across quartiles of homeostatic model assessment for insulin resistance (HOMA-IR) were 1.00, 0.95, 1.34, and 2.25, respectively (P for trend = 0.011). When HOMA-IR was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 1.34 (95% confidence interval 1.16-1.56) for each 1-unit increase in HOMA-IR. Multivariable-adjusted ORs of adverse pregnancy outcomes across quartiles of homeostatic model assessment for β cell function (HOMA-β) were 1.00, 0.51, 0.60, and 0.53, respectively (P for trend = 0.068). When HOMA-β was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 0.57 (95% CI 0.24-0.90) for each 1-unit increase in HOMA-β. However, other quantitative metrics were not associated with the composite adverse pregnancy outcomes.Conclusions: We demonstrated a significant association of β cell function and insulin sensitivity with the risk of adverse pregnancy outcomes. We have provided additional evidence on the early identification of adverse pregnancy outcomes besides the glycemic values.

The relationship between insulin resistance/β-cell dysfunction and diabetic retinopathy in Chinese patients with type 2 diabetes mellitus： the Desheng Diabetic Eye Study

AIM： To investigate the relationship between insulin resistance （IR）/β-cell dysfunction and diabetic retinopathy （DR） in Chinese patients with type 2 diabetes mellitus （T2DM）, and to explore further whether there were differences in the relationship among diabetic patients with higher and lower body mass index （BMI）. METHODS： Cross-sectional study. A total of 1466 subjects with T2DM were recruited in a local Desheng Community of urban Beijing from November 2009 to June 2012 for the cohort of Beijing Desheng Diabetic Eye Study. Standardized evaluation was carried out for each participant, including questionnaire, ocular and anthropometric examinations, and laboratory tests. Seven fields 30° color fundus photographs were used for DR grading according to the Early Treatment Diabetic Retinopathy Study protocols. Homeostatis Model Assessment （HOMA） method was employed for IR and β-cell function assessment. RESULTS： After excluding those participants who were treated with insulin （n=352） or had missing data of fasting insulin （n=96）, and further excluding those with poor quality of retinal photographs （n=10）, a total of 1008 subjects were included for the final analysis, 406 （40.3%） were men and 602 （59.7%） were women, age ranging fiom 34 to 86 （64.87±8.28）y. Any DR （levels 14 and above） was present in 278 （27.6%） subjects. After adjusting for possible covariates, the presence of any DR did not correlate with HOMA IR [odds ratio （OR） 1.51, 95% confidence interval （Cl） 0.87-2.61, P=0.14] or HOMA β-cell （OR 0.71, 95%CI 0.40-1.26, P=0.25）. After stratification by BMI, the presence of any DR was associated positively with HOMA IR （OR 2.46, 95%CI： 1.18-5.12, P=0.016）, and negatively with HOMA β-cell （OR 0.40, 95%CI： 0.19-0.87, P=0.021） in the group of patients with higher BMI （225 kg/m2）. In the group of patients with lower BMI （〈25 kg/m2）, the presence of any DR was not associated with HOMA IR （OR 1.00, 95%C1： 0.43-2.33, P=I.00） or HOMA β-cell （OR 1.41, 95%CI： 0.60-3.32, P=0.43）. CONCLUSION： The data suggest that higher IR and lower 13-cell function are associated with the presence of DR in the subgroup of diabetic patients with higher BMI. However, this association is not statistically significant in diabetic patients with lower BMI.

Long-term exposure to decabrominated diphenyl ether mpairs CD8 T-cell function in adult mice

Polybrominated diphenyl ethers （PBDEs） are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2＇,3,3＇,4,4＇,5,5＇,6,6＇-decabromodiphenyl ether （BDE-209） at doses of 8, 80 or 800 mg/kg of body weight （bw） at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine （IFN-7, IL-2 and TNF-a） production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenesexpressing ovalbumin （rLm-OVA） and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.

Glutamine deprivation impairs function of infiltrating CD8^(+)T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis

BACKGROUND The functions of infiltrating CD8^(+)T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment.Thus,the mechanisms of CD8^(+)T cell dysfunction have become a hot research topic,and there is increased interest on how changes in metabolomics correlate with CD8^(+)T cell dysfunction.AIM To investigate whether and how glutamine metabolism affects the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma.METHODS Immunohistochemical staining and immunofluorescence were performed on surgically resected liver tissues from patients.Differentially expressed genes in infiltrating CD8^(+)T cells in hepatocellular carcinoma were detected using RNA sequencing.Activated CD8^(+)T cells were co-cultured with Huh-7 cells for 3 d.The function and mitochondrial status of CD8^(+)T cells were analyzed by flow cytometry,quantitative real-time polymerase chain reaction,and transmission electron microscopy.Next,CD8^(+)T cells were treated with the mitochondrial protective and damaging agents.Functional alterations in CD8^(+)T cells were detected by flow cytometry.Then,complete medium without glutamine was used to culture cells and their functional changes and mitochondrial status were detected.RESULTS There were a large number of infiltrating PD-1+CD8^(+)T cells in liver cancer tissues.Next,we cocultured CD8^(+)T cells and Huh-7 cells to explore the regulatory effect of hepatoma cells on CD8^(+)T cells.Flow cytometry results revealed increased PD-1 expression and decreased secretion of perforin(PRF1)and granzyme B(GZMB)by CD8^(+)T cells in the co-culture group.Meanwhile,JC-1 staining was decreased and the levels of reactive oxygen species and apoptosis were increased in CD8^(+)T cells of the co-culture group;additionally,the mitochondria of these cells were swollen.When CD8^(+)T cells were treated with the mitochondrial protective and damaging agents,their function was restored and inhibited,respectively,through the mitochondrial damage and apoptotic pathways.Subsequently,complete medium without glutamine was used to culture cells.As expected,CD8^(+)T cells showed functional downregulation,mitochondrial damage,and apoptosis.CONCLUSION Glutamine deprivation impairs the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma through the mitochondrial damage and apoptotic pathways.

Decreased b-Cell Function is Associated with Cardiovascular Autonomic Neuropathy in Chinese Patients Newly Diagnosed with Type 2 Diabetes

The influence of b-cell function on cardiovascular autonomic neuropathy(CAN), an important diabetesrelated complication, is still unclear. In this study, we aimed to investigate the association between residual b-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN? group(diabetic patients with CAN, n = 20) and a CAN-group(diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured.Homeostasis model assessment-beta cells(HOMA-B) and HOMA-insulin resistance(IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN-group, the CAN? group had significantly lower fasting plasma insulin(6.60 ± 4.39 vs 10.45 ± 7.82 l/L, P = 0.029), fasting C-peptide(0.51 ± 0.20 vs0.82 ± 0.51 nmol/L, P = 0.004), and HOMA-B(21.44 ± 17.06 vs 44.17 ± 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio(r = 0.24, P = 0.043) and the 30:15 test(r = 0.26,P = 0.023). Further analysis showed that fasting C-peptide(OR: 0.041, 95% CI 0.003–0.501, P = 0.012) and HOMAB(OR: 0.965, 95% CI 0.934–0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values \ 0.67 nmol/L were more likely to have CAN than those with C-peptide levels C0.67 nmol/L(OR:6.00, 95% CI 1.815–19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased b-cell function was closely associated with CAN in this population.